8.1 Oral drug delivery
11 min read•august 20, 2024
Oral drug delivery is a cornerstone of medicinal chemistry. It involves the complex process of getting drugs from the mouth into the bloodstream. Understanding , dosage forms, and release mechanisms is crucial for designing effective treatments.
Formulation strategies and excipients play key roles in overcoming challenges like poor solubility and metabolism. Innovative delivery systems, such as and lipid-based formulations, are pushing the boundaries of what's possible in oral drug administration.
Oral drug absorption
- Oral drug absorption is a critical aspect of medicinal chemistry as it determines the extent and rate at which a drug enters the systemic circulation
- Factors such as physicochemical properties, formulation characteristics, and physiological conditions influence the absorption of drugs from the gastrointestinal tract
- Understanding the mechanisms and pathways of oral drug absorption is essential for designing effective oral dosage forms and optimizing drug delivery
Factors affecting absorption
Top images from around the web for Factors affecting absorption
Frontiers | Chemokine Function in Periodontal Disease and Oral Cavity Cancer | Immunology View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
Frontiers | Chemokine Function in Periodontal Disease and Oral Cavity Cancer | Immunology View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
1 of 3
Top images from around the web for Factors affecting absorption
Frontiers | Chemokine Function in Periodontal Disease and Oral Cavity Cancer | Immunology View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
Frontiers | Chemokine Function in Periodontal Disease and Oral Cavity Cancer | Immunology View original
Is this image relevant?
Frontiers | Advances in Oral Drug Delivery View original
Is this image relevant?
1 of 3
- Physicochemical properties of the drug (solubility, permeability, pKa, molecular size, and lipophilicity) significantly impact its absorption
- Formulation factors (excipients, dosage form design, and manufacturing process) can modulate drug release and absorption
- Physiological factors (pH, gastrointestinal motility, presence of food, and ) influence the absorption of drugs from the gastrointestinal tract
- Disease states and drug interactions can alter the absorption of oral drugs
Absorption pathways
- Passive is the primary mechanism for the absorption of most drugs, driven by concentration gradients across the intestinal epithelium
- Carrier-mediated transport involves the use of specific transporters (peptide transporters, organic anion transporters) for the absorption of certain drugs
- Paracellular transport occurs through the tight junctions between epithelial cells and is limited to small, hydrophilic molecules
- Endocytosis and transcytosis play a role in the absorption of macromolecules and nanoparticulate systems
Bioavailability of oral drugs
- refers to the fraction of the administered dose that reaches the systemic circulation unchanged
- Oral bioavailability is influenced by factors such as incomplete absorption, presystemic metabolism, and first-pass effect
- Strategies to improve bioavailability include enhancing solubility, permeability, and stability, as well as reducing presystemic metabolism
- Bioavailability studies are essential for assessing the performance of oral dosage forms and establishing bioequivalence
Oral dosage forms
- Oral dosage forms are the most common and convenient route of drug administration, offering advantages such as ease of use, patient compliance, and cost-effectiveness
- The choice of oral dosage form depends on factors such as drug properties, therapeutic goals, and patient characteristics
- Different types of oral dosage forms (, , , and novel systems) offer unique advantages and challenges in terms of drug delivery and patient acceptability
Tablets
- Tablets are solid dosage forms prepared by compressing a mixture of active ingredients and excipients
- Different types of tablets (immediate release, modified release, orally disintegrating, and chewable) cater to specific therapeutic needs and patient preferences
- Tablet formulation involves the selection of appropriate excipients and manufacturing processes to ensure desired drug release, stability, and performance
- Quality control tests (weight variation, hardness, friability, and ) are performed to ensure the consistency and reliability of tablet formulations
Capsules
- Capsules are solid dosage forms that consist of a shell containing the drug and excipients
- Hard gelatin capsules and soft gelatin capsules are the two main types, differing in their composition and manufacturing process
- Capsules offer advantages such as improved bioavailability, taste masking, and the ability to deliver multiple drugs or dosage forms
- Formulation considerations for capsules include compatibility, flowability, and moisture sensitivity of the fill material
Liquid formulations
- Liquid formulations (solutions, suspensions, emulsions, and syrups) offer advantages such as ease of administration, dose flexibility, and improved patient compliance
- Formulation challenges for liquid dosage forms include chemical and physical stability, taste masking, and microbial contamination
- Excipients used in liquid formulations (solvents, solubilizers, preservatives, and flavoring agents) play a crucial role in ensuring the quality and acceptability of the product
- Packaging and storage considerations are important for maintaining the stability and effectiveness of liquid formulations
Novel oral dosage forms
- Novel oral dosage forms (orally disintegrating tablets, buccal and sublingual tablets, and oral films) are designed to improve patient compliance, enhance drug absorption, and target specific sites of action
- Orally disintegrating tablets (ODTs) rapidly disintegrate in the oral cavity, offering convenience for patients with swallowing difficulties (pediatric and geriatric populations)
- Buccal and sublingual tablets are designed to deliver drugs through the mucosa of the cheeks or under the tongue, bypassing first-pass metabolism and providing rapid onset of action
- Oral films are thin, flexible strips that dissolve rapidly in the oral cavity, offering advantages such as improved bioavailability and patient compliance
Drug release mechanisms
- Drug release mechanisms describe the processes by which a drug is released from the dosage form and becomes available for absorption
- The choice of drug release mechanism depends on factors such as therapeutic goals, drug properties, and patient needs
- Different release mechanisms (immediate release, controlled release, sustained release, and delayed release) offer unique advantages and challenges in terms of drug delivery and patient outcomes
Immediate release
- Immediate release dosage forms are designed to release the drug rapidly after administration, providing a quick onset of action
- Disintegration and dissolution are the key processes involved in the release of drugs from immediate release dosage forms
- Excipients such as and solubilizers are used to facilitate the rapid release of drugs from immediate release formulations
- Immediate release dosage forms are suitable for drugs with a wide therapeutic index and short half-life
Controlled release
- Controlled release dosage forms are designed to release the drug at a predetermined rate, maintaining therapeutic concentrations over an extended period
- Mechanisms of controlled release include diffusion, dissolution, osmosis, and ion exchange
- Matrix systems (hydrophilic, hydrophobic, and inert) and reservoir systems (membrane-controlled and osmotic) are commonly used for controlled release formulations
- Controlled release dosage forms offer advantages such as reduced dosing frequency, improved patient compliance, and minimized side effects
Sustained release
- Sustained release dosage forms are designed to release the drug slowly over an extended period, maintaining therapeutic concentrations with minimal fluctuations
- Mechanisms of sustained release include diffusion, , and combination of both
- Polymeric matrices (hydrophilic and hydrophobic) and multi-particulate systems (pellets and beads) are commonly used for sustained release formulations
- Sustained release dosage forms are suitable for drugs with a narrow therapeutic index and a long half-life
Delayed release
- Delayed release dosage forms are designed to release the drug at a specific site or time in the gastrointestinal tract
- Enteric coating is a common approach for delayed release, protecting the drug from the acidic environment of the stomach and releasing it in the intestine
- Time-controlled release systems (pulsatile and chronotherapeutic) are designed to release the drug at a predetermined time or in response to circadian rhythms
- Delayed release dosage forms are suitable for drugs that are unstable in the stomach, cause gastric irritation, or require local action in the intestine
Excipients in oral formulations
- Excipients are inactive ingredients used in oral formulations to facilitate drug delivery, improve stability, and enhance patient acceptability
- The selection of excipients depends on factors such as drug properties, dosage form type, and manufacturing process
- Different classes of excipients (, , disintegrants, lubricants, and coatings) play specific roles in the formulation and performance of oral dosage forms
Fillers and diluents
- Fillers and diluents are used to increase the bulk of the formulation, improve flow properties, and facilitate compression
- Examples of fillers and diluents include lactose, microcrystalline cellulose, and calcium phosphate
- The choice of filler or diluent depends on factors such as compatibility with the drug, flowability, and compressibility
- The particle size and morphology of fillers and diluents can influence the dissolution and bioavailability of the drug
Binders
- Binders are used to promote cohesion and improve the mechanical strength of tablets and granules
- Examples of binders include starch, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC)
- Binders can be added dry or as a solution, depending on the formulation and manufacturing process
- The concentration and type of binder can influence the hardness, friability, and disintegration of the dosage form
Disintegrants
- Disintegrants are used to promote the breakup of the dosage form and facilitate drug release
- Examples of disintegrants include croscarmellose sodium, sodium starch glycolate, and crospovidone
- Disintegrants work by various mechanisms, such as swelling, wicking, and deformation
- The choice and concentration of disintegrant can influence the disintegration time and drug release profile of the dosage form
Lubricants and glidants
- Lubricants are used to reduce friction during tablet compression and prevent sticking to the punch and die
- Examples of lubricants include magnesium stearate, stearic acid, and talc
- Glidants are used to improve the flow properties of the powder blend and prevent segregation
- Examples of glidants include colloidal silicon dioxide and talc
- The concentration and type of lubricant and glidant can influence the hardness, friability, and dissolution of the dosage form
Coatings and film formers
- Coatings are used to modify the appearance, taste, and release characteristics of oral dosage forms
- Examples of coating materials include polymers (cellulose derivatives, acrylates), sugars, and proteins
- Film formers are used to create thin, uniform films on the surface of the dosage form
- Examples of film formers include hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyethylene glycol (PEG)
- The choice and concentration of coating and film-forming materials can influence the drug release, stability, and patient acceptability of the dosage form
Formulation strategies
- Formulation strategies are approaches used to overcome the challenges associated with oral drug delivery and optimize the performance of oral dosage forms
- The selection of formulation strategies depends on factors such as drug properties, therapeutic goals, and patient needs
- Different formulation strategies (solubility enhancement, permeability improvement, stability optimization, and taste masking) are employed to address specific challenges and improve the efficacy and acceptability of oral drugs
Solubility enhancement techniques
- Solubility enhancement techniques are used to improve the dissolution and bioavailability of poorly water-soluble drugs
- Examples of solubility enhancement techniques include particle size reduction (micronization and nanonization), solid dispersions, complexation, and lipid-based systems
- Particle size reduction increases the surface area and dissolution rate of the drug
- Solid dispersions involve dispersing the drug in a hydrophilic carrier matrix to improve wettability and dissolution
- Complexation with cyclodextrins or other agents can enhance the solubility and stability of the drug
- Lipid-based systems (lipid solutions, emulsions, and self-emulsifying drug delivery systems) can improve the solubilization and absorption of lipophilic drugs
Permeability improvement approaches
- Permeability improvement approaches are used to enhance the absorption of drugs across the intestinal epithelium
- Examples of permeability improvement approaches include prodrugs, absorption enhancers, and P-glycoprotein (P-gp) inhibitors
- Prodrugs are inactive derivatives of the drug that undergo enzymatic or chemical transformation in the body to release the active moiety
- Absorption enhancers (surfactants, fatty acids, and chitosan) can temporarily disrupt the intestinal epithelial tight junctions or increase membrane fluidity to facilitate drug absorption
- P-gp inhibitors (verapamil, cyclosporine A) can block the efflux of drugs by the P-glycoprotein transporter, enhancing their absorption and bioavailability
Stability optimization
- Stability optimization is essential for ensuring the quality, safety, and efficacy of oral dosage forms throughout their
- Approaches for stability optimization include the selection of appropriate excipients, packaging materials, and storage conditions
- Antioxidants and chelating agents can be used to prevent oxidative and catalytic of the drug
- pH modifiers and buffer systems can be employed to maintain the optimal pH for drug stability
- Moisture-resistant packaging materials and desiccants can be used to protect the dosage form from humidity and hydrolytic degradation
- Storage conditions (temperature, light, and humidity) should be controlled to minimize drug degradation and ensure product stability
Taste masking methods
- Taste masking methods are used to improve the palatability and patient acceptability of oral dosage forms, particularly for pediatric and geriatric populations
- Examples of taste masking methods include flavoring, sweetening, coating, and microencapsulation
- Flavoring agents (fruit and mint flavors) and sweeteners (sucrose, aspartame) can be added to the formulation to mask the unpleasant taste of the drug
- Coating the drug particles or the dosage form with polymers (Eudragit, cellulose derivatives) can create a barrier between the drug and the taste buds
- Microencapsulation involves encapsulating the drug particles in a polymeric matrix or coating to prevent their interaction with the taste buds
- Ion exchange resins can be used to bind the drug and prevent its release in the oral cavity, thus minimizing the bitter taste
Oral drug delivery challenges
- Oral drug delivery faces various challenges that can impact the absorption, bioavailability, and therapeutic efficacy of drugs
- These challenges arise from the complex nature of the gastrointestinal tract, drug properties, and patient factors
- Understanding and addressing these challenges is crucial for the successful development and optimization of oral dosage forms
Poor solubility and permeability
- Poor solubility and permeability are major challenges for the oral delivery of many drugs, particularly those belonging to BCS Class II and IV
- Low solubility can result in incomplete dissolution and limited absorption of the drug
- Poor permeability can hinder the transport of the drug across the intestinal epithelium, leading to low bioavailability
- Strategies to overcome poor solubility and permeability include the use of solubility enhancement techniques, permeability improvement approaches, and novel drug delivery systems
Presystemic metabolism
- Presystemic metabolism, also known as first-pass metabolism, refers to the metabolic degradation of the drug before it reaches the systemic circulation
- The liver and intestinal enzymes (cytochrome P450, glucuronosyltransferases) are the primary sites of presystemic metabolism
- Presystemic metabolism can significantly reduce the bioavailability of drugs that undergo extensive first-pass effect
- Strategies to minimize presystemic metabolism include the use of prodrugs, enzyme inhibitors, and alternative routes of administration (buccal, sublingual)
Efflux transporters
- Efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are membrane proteins that actively pump drugs out of the intestinal cells
- Efflux transporters can limit the absorption and bioavailability of drugs that are substrates for these proteins
- Overexpression of efflux transporters can lead to multidrug resistance and therapeutic failure
- Strategies to overcome efflux transporter-mediated challenges include the use of efflux inhibitors, prodrugs, and nanoparticulate systems
Food effects on bioavailability
- Food can have a significant impact on the absorption and bioavailability of oral drugs
- The presence of food can alter the gastric emptying rate, intestinal motility, and pH, which can influence drug dissolution and absorption
- Food can also interact with the drug, forming complexes or chelates that reduce its absorption
- High-fat meals can enhance the solubilization and absorption of lipophilic drugs, while high-fiber meals can reduce the absorption of certain drugs
- Strategies to minimize food effects include the use of modified-release formulations, timing of drug administration relative to meals, and patient education on food-drug interactions
Innovative oral drug delivery systems
- Innovative oral drug delivery systems are designed to overcome the limitations of conventional dosage forms and improve the therapeutic performance of drugs
- These systems employ advanced technologies and materials to enhance drug solubility, permeability, stability, and target-specific delivery
- Examples of innovative oral drug delivery systems include nanoparticulate systems, lipid-based formulations, mucoadhesive systems, and oral modified-release technologies
Nanoparticulate systems
- Nanoparticulate systems are colloidal dispersions with particle sizes ranging from 10 to 1000 nm
- Examples of nanoparticulate systems include polymeric nanoparticles, solid lipid nanoparticles, and nanostructured lipid carriers
- Nanoparticulate systems can improve the solubility, stability, and permeability of poorly water-soluble drugs
- The large surface area and enhanced cellular uptake of nanoparticles can increase the bioavailability and therapeutic efficacy of the drug
- Nanoparticulate systems can also be designed for targeted drug delivery to specific tissues or cells
Lipid-based formulations
- Lipid-based formulations are systems that utilize lipids to solubilize and deliver poorly water-soluble drugs
- Examples of lipid-based formulations include lipid solutions, emulsions, microemulsions, and self-emulsifying drug delivery systems (SEDDS)
Key Terms to Review (24)
Absorption: Absorption is the process by which substances, such as drugs, are taken up into the bloodstream after administration. This process is crucial for determining how much of a drug reaches systemic circulation and its effectiveness. Factors such as the route of administration, chemical properties of the drug, and physiological conditions play a significant role in influencing absorption rates.
Adherence: Adherence refers to the extent to which patients follow prescribed medical treatments, including taking medications as directed and following through with treatment plans. This concept is crucial for ensuring the effectiveness of oral drug delivery systems, as proper adherence can significantly impact drug absorption, therapeutic outcomes, and overall patient health.
Binders: Binders are substances used in the formulation of oral dosage forms that help to hold the ingredients together, ensuring the stability and integrity of the drug product. They play a crucial role in the manufacturing process by improving the flow properties of powders, enhancing tablet hardness, and ensuring uniformity in the distribution of active pharmaceutical ingredients. A good binder not only facilitates processing but also influences the drug's release profile in the body.
Bioavailability: Bioavailability refers to the proportion of a drug or substance that enters the systemic circulation when it is introduced into the body, making it available for therapeutic effect. This concept is crucial because it influences how effectively a drug performs in its intended role, impacting factors like dose-response relationships and absorption rates.
Capsules: Capsules are solid dosage forms of medication that are enclosed in a soluble container or shell, typically made from gelatin. They are designed for oral administration and can either be filled with powdered drugs or liquids, providing a convenient way to deliver medications while masking unpleasant tastes or odors.
Degradation: Degradation refers to the process by which a drug molecule breaks down into smaller components or inactive forms due to various environmental factors. This breakdown can significantly affect the drug's efficacy, stability, and overall therapeutic value when delivered orally, as it may lead to reduced bioavailability and altered pharmacokinetics.
Diffusion: Diffusion is the process by which molecules spread from areas of high concentration to areas of low concentration, driven by their kinetic energy. This natural movement of substances is crucial in drug delivery systems, influencing how quickly and effectively a drug can be absorbed and distributed throughout the body. Understanding diffusion helps in designing formulations that optimize therapeutic effects while minimizing side effects.
Disintegrants: Disintegrants are excipients used in pharmaceutical formulations to facilitate the breakup of tablets or capsules into smaller particles, enhancing the dissolution of the active pharmaceutical ingredient (API) and improving bioavailability. These substances are crucial for ensuring that oral medications dissolve properly in the gastrointestinal tract, allowing for effective drug absorption into the bloodstream.
Dissolution: Dissolution is the process by which a solid substance dissolves in a solvent, leading to the formation of a solution. This process is crucial in determining how drugs behave in the body, affecting their absorption and therapeutic effectiveness. Understanding dissolution helps in designing formulations that ensure drugs are released and absorbed properly, particularly for oral delivery and controlled release systems.
Dosage regimen: A dosage regimen refers to the specific plan or schedule for administering a drug, which includes the dose amount, frequency, and duration of treatment. This concept is essential for ensuring therapeutic effectiveness while minimizing potential toxicity. Understanding the dosage regimen is crucial because it affects the drug's pharmacokinetics, pharmacodynamics, and overall patient outcomes.
Erosion: Erosion refers to the gradual degradation and removal of material from a surface, often influenced by environmental factors. In the context of drug delivery, erosion specifically describes the process by which a drug-containing dosage form, like a tablet or capsule, breaks down in the gastrointestinal tract, releasing the active pharmaceutical ingredient over time. This process is crucial for controlling the rate of drug release, ensuring proper absorption and therapeutic efficacy.
FDA Regulations: FDA regulations are the rules set by the U.S. Food and Drug Administration to ensure the safety, efficacy, and security of drugs, biologics, medical devices, and food products. These regulations govern everything from clinical trials to manufacturing processes, aiming to protect public health and facilitate the approval of new therapies and treatments.
Fillers: Fillers are inert substances added to pharmaceutical formulations to enhance the bulk and improve the consistency of drug products. They serve multiple purposes, such as facilitating the manufacturing process, ensuring uniformity in dosage forms, and enhancing patient acceptability by improving texture and appearance.
First-pass metabolism: First-pass metabolism refers to the process where a drug is metabolized in the liver after it is absorbed from the gastrointestinal tract but before it reaches systemic circulation. This process can significantly reduce the bioavailability of certain medications, as a portion of the drug is transformed into inactive metabolites before it can exert its therapeutic effects.
Formulation stability: Formulation stability refers to the ability of a drug formulation to maintain its physical, chemical, and microbiological properties over time under specified storage conditions. This concept is crucial in ensuring that the medication retains its efficacy and safety throughout its shelf life, especially when delivered orally. Factors like temperature, humidity, light exposure, and the composition of the formulation can significantly influence its stability, impacting drug release and absorption once ingested.
ICH Guidelines: ICH Guidelines refer to a set of international standards developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. These guidelines aim to ensure that pharmaceutical products are developed, manufactured, and marketed in a consistent manner, which is crucial for enhancing drug safety and efficacy. They provide frameworks that help connect various aspects such as bioavailability, controlled release formulations, ADMET predictions, good manufacturing practices, and oral drug delivery to ensure a holistic approach in drug development.
Liposomes: Liposomes are small, spherical vesicles composed of lipid bilayers that can encapsulate drugs and other molecules for delivery within biological systems. They serve as a promising drug delivery system, enhancing the solubility and stability of therapeutic agents while improving their bioavailability and reducing toxicity.
Liquids: Liquids are a state of matter characterized by a definite volume but no fixed shape, taking the shape of their container. In the context of oral drug delivery, liquids play a crucial role as they facilitate the administration and absorption of pharmaceuticals, ensuring that active ingredients can be effectively delivered to the bloodstream.
Microspheres: Microspheres are tiny spherical particles ranging from 1 to 1000 micrometers in diameter, used in drug delivery systems to encapsulate and release therapeutic agents. They can be made from various materials, including polymers and ceramics, and play a crucial role in enhancing the bioavailability and stability of drugs when administered either parenterally or orally.
Nanoparticles: Nanoparticles are ultra-small particles that range from 1 to 100 nanometers in size, often exhibiting unique physical and chemical properties compared to their larger counterparts. Their small size allows for enhanced surface area and reactivity, which can be harnessed in various applications, including drug delivery, diagnostics, and imaging. In particular, they play a significant role in enhancing the efficacy and targeting of therapeutic agents in drug delivery systems.
Permeability Barriers: Permeability barriers are biological membranes that regulate the passage of substances into and out of cells or tissues. They play a crucial role in controlling drug absorption, distribution, and bioavailability, especially in oral drug delivery systems where the gastrointestinal tract must selectively allow beneficial compounds while blocking harmful substances.
Shelf Life: Shelf life refers to the length of time a pharmaceutical product remains effective and safe for use when stored under specified conditions. It is crucial in determining the expiration date of medications, impacting their efficacy and safety during oral drug delivery. Understanding shelf life helps ensure that patients receive medications that are both potent and safe, which is particularly important for oral formulations that rely on stable compounds for therapeutic effectiveness.
Solubility issues: Solubility issues refer to the challenges faced when a substance has limited or inadequate solubility in a given solvent, which can affect its bioavailability and effectiveness as a drug. In drug discovery and delivery, these issues are critical because they influence how well a drug can be absorbed in the body and how efficiently it interacts with its target. Understanding solubility is essential for optimizing drug formulations to ensure that therapeutic agents can reach their desired concentration in the bloodstream and tissues.
Tablets: Tablets are solid dosage forms of medication that are typically designed to be taken orally. They consist of active pharmaceutical ingredients combined with excipients, which help in the formulation and delivery of the drug. Tablets can be produced in various shapes and sizes, and they are often preferred for their convenience, stability, and precise dosing capabilities.